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The identification of metabolomic biomarkers relies on the analysis of large cohorts of patients compared to healthy controls followed by the validation of markers in an independent sample set. Indeed, circulating biomarkers should be causally linked to pathology to ensure that changes in the marker precede changes in the disease. However, this approach becomes unfeasible in rare diseases due to the paucity of samples, necessitating the development of new methods for biomarker identification. The present study describes a novel approach that combines samples from both mouse models and human patients to identify biomarkers of OPMD. We initially identified a pathology-specific metabolic fingerprint in murine dystrophic muscle. This metabolic fingerprint was then translated into (paired) murine serum samples and then to human plasma samples. This study identified a panel of nine candidate biomarkers that could predict muscle pathology with a sensitivity of 74.3% and specificity of 100% in a random forest model. These findings demonstrate that the proposed approach can identify biomarkers with good predictive performance and a higher degree of confidence in their relevance to pathology than markers identified in a small cohort of human samples alone. Therefore, this approach has a high potential utility for identifying circulating biomarkers in rare diseases.

Contains fulltext : 226018.pdf (Publisher’s version ) (Open Access) BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) is a late onset progressive neuromuscular disorder. Although dysphagia is a pivotal sign in OPMD it is still not completely understood. OBJECTIVE: The aim of this study was to systematically investigate oropharyngeal functioning in a large OPMD population. METHODS: Forty-eight genetically confirmed OPMD patients completed questionnaires, performed clinical tests on swallowing, chewing, speaking, tongue strength and bite force, and underwent videofluoroscopy of swallowing. Descriptive statistics was used for all outcomes and logistic regression to investigate predictors of abnormal swallowing. RESULTS: Eighty-two percent reported difficulties with swallowing, 27% with chewing and 67% with speaking. Patients performed significantly worse on all oropharyngeal tests compared to age-matched controls except for bite force. Also asymptomatic carriers performed worse than controls: on chewing time, swallowing speed and articulation rate. During videofluoroscopy, all patients (except one asymptomatic) had abnormal residue and 19% aspirated. Independent predictors of abnormal residue were reduced swallowing capacity for thin liquids (OR 10 mL = 0.93; 20 mL = 0.95) and reduced tongue strength for thick liquids (OR 10 mL = 0.95); 20 mL = 0.90). Aspiration of thin liquids was predicted by disease duration (OR = 1.11) and post-swallow residue with 20 mL (OR = 4.03). CONCLUSION: Next to pharyngeal dysphagia, chewing and speaking are also frequently affected in OPMD patients, even in asymptomatic carriers. Residue after swallowing is a very early sign, while aspiration is a later sign in OPMD. For clinical follow-up monitoring of subjective complaints, swallowing capacity and tongue strength seems relevant.

Contains fulltext : 282655.pdf (Publisher’s version ) (Open Access) INTRODUCTION/AIMS: Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, progressive muscle disease. Quantitative muscle ultrasound (QMUS) assesses structural changes in muscles and is a sensitive biomarker in neuromuscular disorders. Our aim of this study was to determine whether QMUS can detect muscle pathology and can be used as longitudinal imaging biomarker in OPMD. METHODS: Genetically confirmed OPMD patients, recruited by their treating physicians or from the national neuromuscular database, were examined twice, 20 months apart, using QMUS of orofacial and limb muscles, and measurements of functional capacity and muscle strength. Absolute echo intensity (AEI) and muscle thickness of all muscles were analyzed and correlated with clinical data. RESULTS: The tongue, deltoid, iliopsoas, rectus femoris, and soleus muscles showed increased AEI at baseline compared with normal values in 43 OPMD patients, with the rectus femoris being most often affected (51%).The AEI and muscle thickness of 9 of 11 muscles correlated significantly with the motor function measure, 10-step stair test, swallowing capacity, dynamometry, Medical Research Council grade, tongue strength, and bite force (r = 0.302 to -0.711). Between baseline and follow-up, deterioration in AEI was found for the temporalis, tongue, and deltoid muscles, and decreased muscle thickness was detected for the temporalis, masseter, digastric, tongue, deltoid, iliopsoas, and soleus muscles (P

Background and ObjectivesOculopharyngeal muscular dystrophy (OPMD) is a late-onset, progressive muscle disease. Disease progression is known to be slow, but details on the natural history remain unknown. We aimed to examine the natural history of OPMD in a large nationwide cohort to determine clinical outcome measures that capture disease progression and can be used in future clinical trials.MethodsPatients invited by their treating physicians or identified from the national neuromuscular database and invited family members were examined twice 20 months apart with fixed dynamometry; Medical Research Council (MRC) grading; maximum bite force and isometric tongue strength; Motor Function Measure (MFM); 10-step stair test; maximum swallowing, chewing, and speech tasks; and quality of life assessments.ResultsDisease progression was captured by 8 of 18 measures over 20 months in 43 patients with genetically confirmed OPMD. The largest deterioration was seen in deltoid muscle strength (−27% [range −17% to −37%]), followed by the quadriceps (−14% [range −6 to −23%]), iliopsoas (−12.2%), tongue (−9.9%), and MRC sum score (−2.5%). The 10-step stair test (−12.5%), MFM part D1 (−7.1%), and maximum repetition rate of /pa/ (−5.3%) showed a significant decrease as well (all p < 0.05). The Physical Functioning domain of the Short Form-36 Health Survey significantly deteriorated (p = 0.044). No relationship was found between disease progression and genotype or disease duration (p > 0.05).DiscussionDespite the slow disease progression of OPMD, this study showed that several outcome measures detected progression within 20 months. Deltoid muscle strength, measured by fixed dynamometry, showed the greatest decline. These longitudinal data provide clinical outcome measures that can be used as biomarkers in future clinical trials.

Small non-coding microRNAs (miRNAs) are involved in the regulation of mRNA stability. Their features, including high stability and secretion to biofluids, make them attractive as potential biomarkers for diverse pathologies. This is the first study reporting miRNA as potential biomarkers for oculopharyngeal muscular dystrophy (OPMD), an adult-onset myopathy. We hypothesized that miRNA that is differentially expressed in affected muscles from OPMD patients is secreted to biofluids and those miRNAs could be used as biomarkers for OPMD. We first identified candidate miRNAs from OPMD-affected muscles and from muscles from an OPMD mouse model using RNA sequencing. We then compared the OPMD-deregulated miRNAs to the literature and, subsequently, we selected a few candidates for expression studies in serum and saliva biofluids using qRT-PCR. We identified 126 miRNAs OPMD-deregulated in human muscles, but 36 deregulated miRNAs in mice only (pFDR &lt, 0.05). Only 15 OPMD-deregulated miRNAs overlapped between the in humans and mouse studies. The majority of the OPMD-deregulated miRNAs showed opposite deregulation direction compared with known muscular dystrophies miRNAs (myoMirs), which are associated. In contrast, similar dysregulation direction was found for 13 miRNAs that are common between OPMD and aging muscles. A significant age-association (p &lt, 0.05) was found for 17 OPMD-deregulated miRNAs (13.4%), whereas in controls, only six miRNAs (1.4%) showed a significant age-association, suggesting that miRNA expression in OPMD is highly age-associated. miRNA expression in biofluids revealed that OPMD-associated deregulation in saliva was similar to that in muscles, but not in serum. The same as in muscle, miRNA expression levels in saliva were also found to be associated with age (p &lt, 0.05). Moreover, the majority of OPMD-miRNAs were found to be associated with dysphagia as an initial symptom. We suggest that levels of specific miRNAs in saliva can mark muscle degeneration in general and dysphagia in OPMD.

Short tandem repeats (STRs) are scattered throughout the human genome. Some STRs, like trinucleotide repeat expansion (TRE) variants, cause hereditable disorders. Unambiguous molecular diagnostics of TRE disorders is hampered by current technical limitations imposed by traditional PCR and DNA sequencing methods. Here we report a novel pipeline for TRE variant diagnosis employing the massively parallel sequencing (MPS) combined with an opensource software package (FDSTools), which together are designed to distinguish true STR sequences from STR sequencing artifacts. We show that this approach can improve TRE diagnosis, such as Oculopharyngeal muscular dystrophy (OPMD). OPMD is caused by a trinucleotide expansion in the PABPN1 gene. A short GCN expansion, (GCN[10]), coding for a 10 alanine repeat is not pathogenic, but an alanine expansion is pathogenic. Applying this novel procedure in a Dutch OPMD patient cohort, we found expansion variants from GCN[11] to GCN[16], with the GCN[16] as the most abundant variant. The repeat expansion length did not correlate with clinical features. However, symptom severity was found to correlate with age and with the initial affected muscles, suggesting that aging and muscle-specific factors can play a role in modulating OPMD.

Background and objectiveOculopharyngeal muscular dystrophy (OPMD) is a genetic disorder caused by an abnormal expansion of GCN triplets within thePABPN1gene. Previous descriptions have focused on lower limb muscles in small cohorts of patients with OPMD, but larger imaging studies have not been performed. Previous imaging studies have been too small to be able to correlate imaging findings to genetic and clinical data.MethodsWe present cross-sectional, T1-weighted muscle MRI and CT-scan data from 168 patients with genetically confirmed OPMD. We have analysed the pattern of muscle involvement in the disease using hierarchical analysis and presented it as heatmaps. Results of the scans were correlated with genetic and clinical data.ResultsFatty replacement was identified in 96.7% of all symptomatic patients. The tongue, theadductor magnusand thesoleuswere the most commonly affected muscles. Muscle pathology on MRI correlated positively with disease duration and functional impairment.ConclusionsWe have described a pattern that can be considered characteristic of OPMD. An early combination of fat replacement in the tongue,adductor magnusandsoleuscan be helpful for differential diagnosis. The findings suggest the natural history of the disease from a radiological point of view. The information generated by this study is of high diagnostic value and important for clinical trial development.

Although the workhorse of the photovoltaic industry is still the silicon wafer, accounting for 90% of the market, it was early recognized that other semiconductors could make efficient solar cells. Organic-based photovoltaic technology has demonstrated the ability to cross the 10% efficiency barrier and is expected to eventually present lower costs than silicon-based technology, thus becoming a promising alternative. So, what are the strengths and remaining challenges for the thin-film solar cells industry? This article reviews state-of-the-art thin-film solar cells, focusing on dye-sensitized solar cells, and discusses future trends and possibilities of bringing this technology into the market of photovoltaics.

The effect of straight release carbamazepine monotherapy was studied in 12 well-controlled epileptic patients using adaptive tracking, smooth pursuit and saccadic eye movements, body sway, Digit Symbol Substitution Test (DSST) and Visual Analogue Scales. Patients were matched to healthy controls for age and gender. After patients had received their usual morning dose of carbamazepine, patient-control pairs were studied for 7 h. Compared to controls, the average DSST scores of patients were significant lower. No relationships were shown between DSST performance and plasma concentrations of carbamazepine and carbamazepine-epoxide. No significant differences were found for any of the other effect parameters. Variations in plasma concentrations were limited, contributing to the absence of systematic fluctuations in test results. Of the used tests, DSST is most clearly related to cognitive function. It is concluded that the difference in DSST performance appears to reflect a long-term small neurocognitive difference between subjects with and without epilepsy.

Objective: The effect of oral warfarin on the pharmacokinetics and pharmacodynamics of the synthetic direct thrombin inhibitor napsagatran was investigated. Methods: In an open, randomised, two-way crossover study, 12 healthy male volunteers were infused napsagatran (80 µg/min) for 48 h. Each subject was administered 25 mg warfarin (Coumadin) at the start of the infusion in either the first or second treatment period. Sampling was performed regularly over the treatment period and 24 h thereafter for measurement of plasma levels of napsagatran, activated partial thromboplastin time (APTT) and prothrombin time (PT). Results: The pharmacokinetic parameters of napsagatran were not significantly influenced by co-administration of warfarin. Napsagatran administration was followed by increases in APTT and PT. Co-administration of warfarin increased the AUEC (area under the effect curve) calculated for the period 0–48 h (corrected for baseline) for APTT by 45% (95% CI: 28–65%) and for PT by 438% (95% CI: 272–678%) compared to the treatment with napsagatran alone. Conclusion: Warfarin has no effect on the pharmacokinetics of napsagatran, but has a marked influence on the pharmacodynamic parameters (APTT, PT) of napsagatran. In clinical practice, this interaction between the two compounds should be taken into account. The PT cannot be used to monitor the effect of oral anticoagulants during the switch from this group of direct thrombin inhibitors to full oral anticoagulant therapy.

Potential interethnic differences in drug disposition and effects between Japanese and white subjects hamper the registration in Japan of medications already used in Western countries. This double-blind, placebo-controlled, crossover study was conducted to compare the pharmacodynamics and pharmacokinetics of a single oral dose of nitrazepam (5 mg) in age- and sex-matched Japanese (n = 8) and white (n = 8) healthy volunteers. The study was performed in centers in Japan and the Netherlands using the same methods and study design. Subjects were individually matched for gender, age, and body stature. Drug effects were measured by means of saccadic and smooth pursuit eye movements and visual analog lines obtained from the scales of Bond and Lader. There were no pharmacokinetic differences between the Japanese and white subjects. Clearance of nitrazepam was 0.91 +/- 0.165 mL/min/kg and 1.17 +/- 0.492 mL/min/kg, and half-life (t1/2) was 22.1 +/- 4.96 hours and 21.5 +/- 7.51 hours for the Japanese and European groups, respectively. Pharmacokinetic parameters showed no significant correlation with age, height, or weight. The average time-effect curves for the different parameters were comparable between groups. Compared with placebo, both groups showed similar significant reductions in average peak velocity and increases in saccadic inaccuracy and reaction time. Visual analog scores showed clear sedation in the white subjects, but insignificant effects in the Japanese subjects. Smooth pursuit did not change significantly in either group. Slope and intercept of the concentration-effect relationships for saccadic peak velocity showed considerable intersubject variability, but no clear differences between groups. The pharmacokinetics and pharmacodynamics of nitrazepam were similar in matched healthy Japanese and white subjects. Interethnic comparative studies are feasible, and provide meaningful information about potential racial differences in disposition and action of drugs. Such studies can form a rational basis for comparative clinical trials.

Aims Application of single methods to assess liver blood flow (LBF) yielded conflicting results on the magnitude and duration of effect on LBF of oral nifedipine and captopril. The aim of this study was to investigate the influence of these drugs on LBF by simultaneous use of ICG infusion and echo-Doppler. Methods The study was performed according to a double-blind, placebo-controlled, randomized, cross-over design in nine healthy male volunteers. After an overnight fast and an equilibration period, subjects received a continuous i.v. indocyanine green (ICG) infusion for 4 h. At presumed ICG steady state (t=45 min), subjects were dosed with oral nifedipine (20 mg), captopril (50 mg) or placebo. During the experiment, blood sampling for ICG assay and measurement of portal venous blood flow (echo-Doppler) took place regularly. Treatments were compared using analysis of variance. Differences are reported with 95% confidence intervals (CI). Results The area under the curves (AUC) for ICG over 1 h and over 3 h after nifedipine were 15% (difference in AUC: +0.6, +7.0 mg l−1 min) and 22% (+7.0, +28.4 mg l−1 min) lower compared with placebo. After captopril, the AUC values were 8–10% lower compared with placebo but the 95% CIs included zero. Portal venous flow was 15% (+5, +86 ml min−1 ) higher compared to placebo after nifedipine but not after captopril (−3%; −49, +33 ml min−1 ). The duration of effect on liver blood flow lasted approximately 2 h but was variable (range: 40–160 min). The time to maximal blood flow increase and the duration of effect after nifedipine were very similar for both measures of LBF. Changes in ICG concentrations could be reasonably well predicted from the changes in portal blood flow. Conclusions Nifedipine increases LBF for a substantial period of time but the effect is variable between subjects. This effect could be detected by both the ICG method and echo-Doppler and the findings of both methods were in agreement. In this respect it is likely that captopril does not influence LBF in healthy volunteers as no effect was detected with either method.

Annual precipitation on the Caribbean island of Puerto Rico decreased steadily during the 20 century, on average by 16 %. The reduced rainfall manifested itself in the form of regular water rationings during the 1990s which hit millions of inhabitants. Simultaneous with the reduction in rainfall there was widespread deforestation, notably in the coastal lowlands. This paper examines the link between the reduction in precipitation and the land cover change using a combination of energy balance measurements and mesoscale atmospheric modelling. The explanation of the reduction in precipitation appears to be quite different than expected. Based on measurements made earlier over rainforest and pasture in the Amazon, a forest covered island would be expected to be cooler because the higher transpiration -of the forest compared to grasslandtends to cool the surface. During an intensive measurement campaign on Puerto Rico, the opposite appeared to be the case: transpiration by a coastal wetland forest proved to be less than that for a grassland. In addition, the forest albedo was 8 % lower than that for grassland. Together, these two factors caused the sensible heat flux over the forest to be twice as high as that over the grassland, whereas forest evaporation was lower. The surface energy balance observations over forest and grassland were used to derive proper land surface parameterizations, which were implemented in a mesoscale atmospheric circulation model (RAMS) to simulate the meteorological effects of island wide deforestation. The model simulations indicated that the development of a sea breeze during the day dominates climate on the island. Sea breezes develop when the land surface is warmer than the surrounding ocean. In model runs, where the island was assumed to be completely covered with forest, the sea breeze was considerably stronger than in model runs where the vegetation had been transformed to grassland. Along the sea breeze front, convergence caused upward air motions. As this happens more strongly over a forested island, more clouds are formed but at a higher elevation, with an estimated 10-20 % enhancement of precipitation compared to a deforested island. In the deforested scenario the cloud base was typically lowered by 200 m. Refinement of the model is required to obtain more accurate estimates of the changes in precipitation, although most likely the relevant processes have been determined. This project has offered new insights into the effects of climate change and may contribute to improved land use and water resources policies on Puerto Rico.

Pharmacodynamic interactions of low doses of diazepam and alcohol were investigated in a double blind, randomised, 2 x 2 factorial, cross-over study in eight healthy volunteers. Alcohol or glucose 5% were administered intravenously at rates calculated to maintain breath alcohol levels of 0.5 g/l from 1.5 to 5.5 h after starting the alcohol infusion. Diazepam 5 mg or placebo were administered orally at 1.5 h. Evaluation of pharmacodynamic interactions was performed for the average results of tests performed at 2, 3.5 and 5 h. Plasma concentrations of (desmethyl-) diazepam and breath alcohol levels were measured for pharmacokinetic analysis. Breath alcohol reached pseudo steady state levels of 0.38 g/l (range: 0.24-0.57) after alcohol alone and 0.37 g/l (range: 0.27-0.52) in combination with diazepam. Alcohol effects were demonstrated for latency of saccadic eye movements, smooth pursuit eye movements and subjective drug effects. Diazepam impaired smooth pursuit and saccadic eye movements, adaptive tracking, digit symbol substitution and body sway. The effects of combined alcohol and diazepam were mostly additive without significant synergistic interactions. However, in two subjects large supra-additive effects occurred at 3.5 h following alcohol+diazepam, which were not explained by increased drug levels. The design and methods used in this study proved advantageous in evaluating low dose pharmacodynamic interactions. Despite the absence of significant synergistic interactions, unanticipated impairment of performance may occur in susceptible individuals when taking combined low doses of alcohol and diazepam.

SummaryThe influence of changes in liver blood flow on the clearance of rt-PA was studied both in healthy subjects and in a perfused rat liver model. Liver blood flow in healthy subjects was documented indirectly by the clearance of indocyanine green (ICG). Exercise reduced liver blood flow on average by 57% with a 95% confidence interval (95% Cl) ranging from 51% to 62% (n = 5) and increased plasma levels of rt-PA activity (after an i. v. infusion of 18 mg of rt-PA over 120 min) by 119% (95% Cl, 58% - 203%) and rt-PA antigen by 91% (95% Cl, 30% - 140%). In the perfused rat liver model it was shown that halving or doubling of the physiological flow rate of a perfusate, containing rt-PA caused a proportional change in the clearance of rt-PA, while the extraction of rt-PA by the liver remained similar. In conclusion, liver blood flow is a major determinant of the clearance of rt-PA. This may have important implications for dosage of rt-PA in patients with myocardial infarction.

SummaryPotential pharmacokinetic and pharmacodynamic interactions between two oral doses of GR32191 (40 and 80 mg), a new thromboxane antagonist, and heparin (5,000 IU bolus + 1,000 IU/h for 3 h) were studied in eighteen healthy male volunteers using two separate double-blind, randomised, placebo-controlled, cross-over studies.Mean (range) bleeding time values were 8.4 min (7.5–9.7) during heparin/placebo, 12.1 min (9.2–18.6) (GR32191/placebo) and 16.3 min (11.5–21.4) (GR32191/heparin) in the 40 mg study, while these values were 8.7 min (5.5–15.5), 16.0 min (9.3 – >36.0) and 23.8 min (10.7 – >36.0), respectively in the 80 mg study. Compared to screening values, the combination of 80 mg of GR 32191 and heparin had a greater effect on the bleeding time than the sum of the prolongations after the separate treatments (p = 0.05). In the 40 mg study this was not the case. Pharmacokinetics of heparin (as assessed by plasma anti-Xa and antithrombin activity) and GR32191 were unaltered during coadministration of the two drugs. GR32191 did not influence the effects of heparin on APTT. Heparin slightly diminished the inhibition of collagen induced platelet aggregation by 80 mg of GR32191 and the U-46619 (thromboxane A2-mimetic) induced platelet aggregation remained unchanged. Overall fibrinolytic activity (as evaluated by the fibrin plate test) was similar during all three treatments in the study with 80 mg.The combination of 80 mg of GR32191 and heparin caused a prolongation of the bleeding time which was more than expected on the basis of their individual effects.

Application of single methods to assess liver blood flow (LBF) yielded conflicting results on the magnitude and duration of effect on LBF of oral nifedipine and captopril. The aim of this study was to investigate the influence of these drugs on LBF by simultaneous use of ICG infusion and echo-Doppler.The study was performed according to a double-blind, placebo-controlled, randomized, cross-over design in nine healthy male volunteers. After an overnight fast and an equilibration period, subjects received a continuous i.v. indocyanine green (ICG) infusion for 4 h. At presumed ICG steady state (t=45 min), subjects were dosed with oral nifedipine (20 mg), captopril (50 mg) or placebo. During the experiment, blood sampling for ICG assay and measurement of portal venous blood flow (echo-Doppler) took place regularly. Treatments were compared using analysis of variance. Differences are reported with 95% confidence intervals (CI).The area under the curves (AUC) for ICG over 1 h and over 3 h after nifedipine were 15% (difference in AUC: + 0.6, + 7.0 mg l(-1) min) and 22% (+ 7.0, + 28.4 mg l(-1) min) lower compared with placebo. After captopril, the AUC values were 8-10% lower compared with placebo but the 95% CIs included zero. Portal venous flow was 15% (+ 5, + 86 ml min(-1)) higher compared to placebo after nifedipine but not after captopril (-3%; -49, +33 ml min(-1)). The duration of effect on liver blood flow lasted approximately 2 h but was variable (range: 40-160 min). The time to maximal blood flow increase and the duration of effect after nifedipine were very similar for both measures of LBF. Changes in ICG concentrations could be reasonably well predicted from the changes in portal blood flow.Nifedipine increases LBF for a substantial period of time but the effect is variable between subjects. This effect could be detected by both the ICG method and echo-Doppler and the findings of both methods were in agreement. In this respect it is likely that captopril does not influence LBF in healthy volunteers as no effect was detected with either method.

Turbulent fluctuations have been investigated in the internal boundary layer (IBL) which forms after a dry-to-wet surface transition. The IBL is defined as that part of the atmospheric surface layer where the influence of the downstream surface is noticeable. The results of the application of three different quadrant analysis techniques are presented. The three techniques, in increasing order of the amount of information supplied, provide: The results show that in the IBL the vertical flux of sensible heat is maintained by (i) a small fraction of large samples with warm air carried upwards, and (ii) a larger fraction of small samples with cool air carried downwards. Both processes are almost equal in importance. In the morning and near the top of the IBL negative temperature fluctuations are limited by the near-uniform temperature conditions upstream and above the IBL. This limitation reduces, at that location, the conditional average of the sinking motions of cool air. Closer to the wet surface the negative temperature fluctuations are less susceptible to the above mentioned limitation. As a consequence contributions from all four quadrants are almost equal leading to a very small vertical heat flux. In the presence of a temperature inversion over both the upstream and the downstream terrain, shear-generated turbulence appears to be the cause of the relative abundance of sinking motions of warm air and rising motions of cool air, leading to a reversal of the sensible heat flux. The latent heat flux is positive (i.e. directed away from the surface) at all times and is maintained in almost equal amount by (i) a small number of large magnitude samples with moist air carried upwards, and (ii) small magnitude samples with sinking motions of dry air. These sinking motions of dry air are far more numerous, especially in the morning, but their conditional average is very small. The abundance of sinking motions of dry air is attributed to the fact that over the downstream terrain evaporation is greatly enhanced, leading to a skewed w′q′ signal. This skewness is clearly visible in the w′q′-probability density distribution of the morning runs. In the evening the asymmetry between these two different contributions disappears. This is because evaporation is greatly reduced and large positive humidity fluctuations no longer occur.

1. In a previous study it was demonstrated that a decrease in liver blood flow produced a decrease in clearance of recombinant human tissue-type plasminogen activator (rt-PA). 2. The purpose of this randomized, double-blind, placebo-controlled, three-way, cross-over investigation was to determine the effect of nifedipine (20 mg orally), a compound that increases liver blood flow, on plasma concentrations of steady state endogenous and recombinant tissue-type plasminogen activator (t-PA and rt-PA) (35 mg of rt-PA over 2 h) in nine healthy male volunteers. 3. Nifedipine increased liver blood flow by 95% (42-167%) (mean (95% confidence interval)) as assessed by indocyanine green (ICG, 0.5 mg kg-1 i.v. bolus injection) clearance. 4. Nifedipine did not influence the plasma concentrations of total rt-PA antigen and activity as evaluated by the areas under the rt-PA curves from 30 min (time at which nifedipine was ingested) to 90 min during the rt-PA infusion (P > 0.05) and by analysis of a possible treatment x time interaction (P > 0.05). In addition, the plasma concentrations of endogenous t-PA remained unchanged when nifedipine was given alone. 5. In conclusion, by using nifedipine as a model compound it was demonstrated that the combination of rt-PA and a compound which increases liver blood flow probably does not lead to substantial changes in plasma concentrations of rt-PA.

The effects of heparin (5,000 IU i.v.) and the low molecular weight heparinoid Org 10172 (Orgaran) (3,250 anti-Xa units i.v.) on components of the fibrinolytic system were studied in two double-blind, randomised, placebo-controlled, cross-over trials using healthy subjects. In study A (n = 6) the effects were studied during rest and standardized exercise and in study B (n = 6) during a low dose infusion of recombinant tissue-type plasminogen activator (rt-PA; 80 micrograms over 16 min). At rest, heparin and Org 10172 did not influence the plasma concentrations of endogenous t-PA antigen and activity, urokinase-type PA (u-PA) antigen, plasmin activatable pro-urokinase (scu-PA), active urokinase (tcu-PA) and plasminogen activator inhibitor-1 (PAI-1) antigen. Recombinant t-PA antigen and activity during rt-PA infusion were also not affected. During exercise, neither heparin nor Org 10172 influenced the area under the curve (AUC) of t-PA and u-PA antigen and t-PA activity when compared with placebo. Unexpectedly, after heparin the AUC of t-PA activity was 49% larger (range +19 to +245%) than after Org 10172 (p0.05). The last difference was considered spurious, scu-PA, tcu-PA and PAI-1 antigen levels at 2 min after termination of exercise were unaffected by both compounds (p0.05). Sulphated polysaccharides do not increase fibrinolytic activity of the plasma by changing the concentrations of the components of the fibrinolytic system.

BACKGROUND In this study, the anticoagulant response of 12,500 IU heparin s.c. was investigated in patients with myocardial infarction and healthy volunteers to determine variabilities in response and modifying factors. METHODS AND RESULTS On the fourth day after thrombolytic therapy, blood samples were taken before and at frequent intervals until 10 hours after the injection of 12,500 IU heparin s.c. Plasma anti-Xa activity, anti-IIa activity, and the activated partial thromboplastin time (APTT) were measured in addition to body weight and thickness of the abdominal subcutaneous fat layer. Contrary to expectations, the increase of anti-Xa activity, anti-IIa activity, and APTT compared with baseline (predrug) levels was very small, with an average maximal APTT of 42.6 seconds (SD, 12.4 seconds; range, 30.4-70.7 seconds). Subsequently, the influence of the length of the injection needle on the anticoagulant effect of 12,500 IU heparin s.c. was studied in 10 healthy volunteers to find a factor that could be responsible for the poor response in the patients. The length of the injection needle did not influence the anticoagulant effect of heparin. Large interindividual and intraindividual variabilities were seen in the volunteers. The majority of volunteers had minimal prolongation of the APTT, but very strong prolongation was also seen (maximal APTT, 163 seconds). There was no correlation between the abdominal skinfold thickness and anti-Xa activity, anti-IIa activity, or APTT (p > 0.05), but in the patient study, there was a correlation between weight and anti-Xa activity and anti-IIa activity (p < 0.05), and in the volunteer study, there was a correlation between weight and anti-Xa activity and APTT (p < 0.05). CONCLUSIONS Subcutaneous administration of heparin in a fixed dose for prophylactic and therapeutic purposes may be inadequate because of the large interindividual and intraindividual variations in anticoagulant effect.

SummaryThe effects of heparin (5,000 IU i.v.) and the low molecular weight heparinoid Org 10172 (Orgaran®) (3,250 anti-Xa units i. v.) on components of the fibrinolytic system were studied in two double-blind, randomised, placebo-controlled, cross-over trials using healthy subjects. In study A (n = 6) the effects were studied during rest and standardized exercise and in study B (n = 6) during a low dose infusion of recombinant tissue-type plasminogen activator (rt-PA; 80 µg over 16 min). At rest, heparin and Org 10172 did not influence the plasma concentrations of endogenous t-PA antigen, and activity, urokinase-type PA (u-PA) antigen, plasmin activatable pro-urokinase (scu-PA), active urokinase (tcu-PA) and plasminogen activator inhibitor-1 (PAI-1) antigen. Recombinant t-PA antigen and activity during rt-PA infusion were also not affected. During exercise, neither heparin nor Org 10172 influenced the area under the curve (AUC) of t-PA and u-PA antigen and t-PA activity when compared with placebo. Unexpectedly, after heparin the AUC of t-PA activity was 49% larger (range +19 to +245%) than after Org 10172 (p 0.05). Sulphated polysaccharides do not increase fibrinolytic activity of the plasma by changing the concentrations of the components of the fibrinolytic system.

Objective To investigate the prevalence of distinct combinations of components of the metabolic syndrome among adolescents. Design A complex, multistage, stratified geographic area design for collecting representative data from the noninstitutionalized US population. Setting The NHANES, an ongoing surveillance of the nation's health conducted by the Centers for Disease Control and Prevention. Participants Two thousand four hundred fifty-six Hispanic, white, and black adolescents aged 12 to 19 years observed in the 2001-2002, 2003-2004, and 2005-2006 NHANES data releases. Main Outcome Measures Metabolic syndrome was defined as having 3 or more disorders in the following measurements: waist circumference, blood pressure, fasting triglycerides, high-density lipoprotein serum cholesterol, and glucose. Results About half of the participants had at least 1 disordered measurement, with an overall metabolic syndrome prevalence of 8.6% (95% confidence interval, 6.5%-10.6%). Prevalence was higher in males (10.8%) than females (6.1%), and in Hispanic (11.2%) and white (8.9%) individuals than in black individuals (4.0%). In black females, there was a high prevalence of a large waist circumference (23.3%), but no component of metabolic syndrome dominated its diagnosis in black adolescents of either sex. A large waist circumference and high fasting triglyceride and low high-density lipoprotein serum cholesterol concentrations were salient factors in Hispanic and white adolescents of both sexes; high glucose concentrations were prominent among Hispanic and white males. Conclusion The low prevalence of metabolic syndrome in black adolescents, in parallel with uniformly low prevalence of all 5 risk factors among those with metabolic syndrome, portend ethnic disparities in the time table for early onset of cardiometabolic disorders.

The absorption of high and low molecular fractions of heparin from the subcutaneous compartment was evaluated in eight healthy males. They were given an intravenous infusion of 4000 U calcium heparin in 4 hours and on another occasion a subcutaneous injection of 12,500 U calcium heparin (washout period of 1 week). Anticoagulation was monitored by anti-Xa, antithrombin activity, and activated partial thromboplastin time. To evaluate factors that might influence absorption, body weight, body fat, and abdominal skinfold thickness were recorded. There was a pronounced inter-individual variability in absorption but the absorption of the two fractions of heparin was similar. The highly variable absorption was related to the abdominal skinfold thickness, and this could have implications for therapeutic and prophylactic heparin regimens.

Forty patients with uncomplicated essential hypertension were investigated with respect to diurnal variability of arterial pressure (indirect recordings), intra-arterial pressure, cardiac output, plasma volume, renal plasma flow and glomerular filtration rate. Extracellular volume was estimated in 17, plasma renin concentration in 33 and vector-cardiograms were recorded in 27 patients. Treatment was discontinued at least a fortnight before and sodium intake was standardized.—Blood pressure varied across a wide range. Variability (lability) of blood pressure was quantified by expressing the difference between highest and lowest automatic blood pressure readings as a percentage of the highest reading. Cardiac output correlated with variability of blood pressure, blood volume and renal blood flow.—Plasma renin concentration was correlated with renal vascular resistance and filtration fraction.—QRS magnitude appeared to be related with the level of arterial pressure.—Haemodynamic variables exhibited a definite relationship with age, deviating in part from distribution according to age in normal populations.

During the years 1968-71 203 patients with proved myocardial infarction were admitted to the trial. Patients were mobilized either on day 10 (102 patients) or on day 20 (100 patients). All patients were kept in hospital for 30 days in order to ensure a detailed comparison of clinical course and laboratory data. In neither group was there a fatal complication and the differences in clinical outcome or laboratory data were statistically not significant. Half of the patients from each group were re-examined after an average of one-and-a-half years, and again no differences were observed. It is concluded that patients with an uncomplicated myocardial infarction may safely be mobilized after 9 days and discharged after three weeks.

1. Endogenous fibrinolytic capacity increases after administration of 1-desamino-8-d-vasopressin. This increase is commonly attributed to an increase in release of tissue-type plasminogen activator from the endothelium. However, the possibility that 1-desamino-8-d-vasopressin influences liver blood flow, which is a major determinant of tissue-type plasminogen activator clearance, cannot be ruled out. 2. The influence of 1-desamino-8-d-vasopressin on haemodynamics, liver blood flow and fibrinolytic parameters was investigated in a randomized double-blind cross-over study in nine healthy male subjects (age 20–26 years). 3. 1-Desamino-8-d-vasopressin exerted significant haemodynamic effects: mean arterial pressure decreased maximally 12 (95% confidence interval 8–15) mmHg and heart rate increased maximally 21 (95% confidence interval 15–27) beats/min. 4. Endogenous fibrinolytic parameters increased after administration of 1-desamino-8-d-vasopressin. Both tissue-type plasminogen activator antigen and tissue-type plasminogen activator activity were elevated and showed the maximal response shortly after drug administration was completed. 5. 1-Desamino-8-d-vasopressin increased portal venous blood flow as measured with echo-Doppler. The maximal increase in mean blood flow of 55 (95% confidence interval 19–92)% was observed at the end of the 1-desamino-8-d-vasopressin infusion and coincided with the maximal changes in systemic haemodynamics and fibrinolytic parameters. The increase in portal blood flow was not reflected in significant changes in Indocyanine Green clearance. It appears that the Indocyanine Green method is relatively insensitive to increases in liver blood flow. 6. The observed increase in fibrinolytic activity due to tissue-type plasminogen activator activity after 1-desamino-8-d-vasopressin administration may be due to an increased release of tissue-type plasminogen activator from the endothelium and is not caused by changes in clearance.